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Cyclic vomiting syndrome (CVS) clinical guidelines recommend an algorithm of basic testing for standard patients, and more targeted testing, including laboratory and imaging studies, in the presence of specific red flags. The cost-effectiveness of this screening of children with suspected CVS is lacking. The objectives of this study are to determine whether screening studies in CVS patients results in diagnostic change and to estimate their healthcare cost.Charts of patients (1–18 years) with suspected CVS were retrospectively reviewed at a single center. Results and cost of laboratory and imaging studies were analyzed.A total of 503 charts were reviewed from electronic medical records with the International Classification of Diseases-9 (ICD-9) code 536.2 or search terms “CVS, cyclic vomiting, persistent emesis/vomiting, hyperemesis, or intractable/ periodic vomiting.” Of these, 165 (33%) had a diagnosis of CVS and 135 (82%) children (mean age 7.7 ± 4.3; 73 (54%) girls) met CVS criteria based on North American Society for Pediatric Gastroenterology, Hepatology and Nutrition diagnostic criteria. Of those meeting CVS criteria, 6 (4%) had a change in management based on the CVS screening evaluation. The mean cost of screening per patient that met CVS criteria was $6125.02 and the estimated total cost for all patients who met CVS criteria was $826,877.88.The screening metabolic laboratory results, pelvic ultrasound, magnetic resonance imaging, and upper endoscopy resulted in a diagnosis change in few patients screened for CVS. Most children who met criteria for CVS did not benefit from screening evaluation as results did not change clinical diagnosis or management, and were associated with higher cost.